Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 611399

SODIUM CHANNEL AND CLATHRIN LINKER 1; SCLT1

Alternative titles; symbols

CLATHRIN-ASSOCIATED PROTEIN 1A; CAP1A

HGNC Approved Gene Symbol: SCLT1

Cytogenetic location: 4q28.2 Genomic coordinates (GRCh38) : 4:128,873,241-129,093,539 (from NCBI)

TEXT

Description

SCLT1 acts as a linker protein between the voltage-gated sodium channel Na(v)1.8 (SCN10A; 604427) and clathrin (see CLTC, 118955) (Liu et al., 2005).

Cloning and Expression

Using yeast 2-hybrid analysis with the C terminus of rat Scn10a as bait to screen a rat brain cDNA library, Liu et al. (2005) cloned rat Sclt1, which they called CAP1A. By database analysis, they identified the mouse and human SCLT1 sequences. The deduced 688-amino acid human SCLT1 protein shares 76% sequence identity with the rat protein. SCLT1 contains a myosin tail domain (MTD), a vacuolar ATPase homology domain (V-pump), and dileucine motifs in the C terminal terminus. SCLT1 lacks a signal peptide and transmembrane segments. Immunofluorescence studies detected rat Sclt1 protein in dorsal root ganglion (DRG) neurons and sciatic nerve C-type fibers with low immunostaining in the cerebellum. No signal was detected in liver or heart. Immunostaining studies colocalized rat Sclt1 with Scn10a in DRG neurons and with clathrin within subsurface regions of the DRG.

Gene Function

Using yeast 2-hybrid analysis, GST pull-down assays, and coimmunoprecipitation assays of full-length and truncated forms of rat Sclt1 and Scn10a, Liu et al. (2005) showed that Sclt1-Scn10a interaction requires the Sclt1 MTD and the Scn10a conserved region-1 (amino acids 1724-1788). GST pull-down assays revealed that the rat Sclt1 C-terminal domain (CTD) bound clathrin. Protein binding assays followed by SDS-PAGE and immunoblotting demonstrated that an Scn10a-Sclt1 complex bound clathrin, whereas Scn10a alone had no direct interaction with clathrin. Liu et al. (2005) concluded that Sclt1 acts as a linker protein that binds clathrin and Scn10a in a multiprotein complex. Cotransfection of Scn10a and Sclt1 demonstrated that overexpression of Sclt1 selectively reduced the amplitude of the Scn10a current; this reduction was inhibited by the addition of bafilomycin A1, an inhibitor of vacuolar H+ ATPases. Liu et al. (2005) concluded that Slct1 regulation of Scn10a current may involve endocytotic processes.

Gene Structure

Liu et al. (2005) determined that the SCLT1 gene contains 20 exons.

Molecular Genetics

In a male with significant multisystem organ involvement suggestive of a ciliopathy, born to consanguineous Saudi parents, Adly et al. (2014) reported a homozygous splice site mutation in the SCLT1 gene (611399.0001).

ALLELIC VARIANTS 1 Selected Example):

.0001 VARIANT OF UNKNOWN SIGNIFICANCE

SCLT1, IVS5, T-C, +2
SNP: rs587777504, ClinVar: RCV000128556, RCV003987368

This variant is classified as a variant of unknown significance because its contribution to orofaciodigital syndrome IX (258865) has not been confirmed.

In a Saudi boy, born of healthy consanguineous parents, with a severe ciliopathy phenotype featuring midline cleft, microcephaly, and colobomatous microphthalmia/anophthalmia, Adly et al. (2014) detected a homozygous splice site mutation in the SCLT1 gene (c.290+2T-C) using exome sequencing. The boy had severe midline cleft lip and palate, microcephaly, and choanal atresia. He also had significant eye involvement in the form of severe coloboma, and atrial septal defect (ASD) and ventricular septal defect (VSD). He had micropenis but not ambiguous genitalia. Brain imaging revealed pachygyria and absent corpus callosum. Inner ear structures were abnormal. He died at 3 months of age following a severe respiratory tract infection. The mutation completely abolished the consensus donor site of exon 5; RT-PCR showed complete skipping of exon 5 resulting in a frameshift and introduction of a premature stop codon (Lys79ValfsTer4). There was no evidence of nonsense-mediated decay (NMD). This mutation was not found in 250 in-house Saudi exomes, by Sanger sequencing of 96 Saudi controls, or in the dbSNP, 1000 Genomes, or Exome Variant Server databases. Adly et al. (2014) considered the severe ciliopathy phenotype of their patients to best fit OFD type IX in view of the prominent eye involvement, although the patients lacked the classic tongue involvement (Gurrieri et al., 2007).

REFERENCES

Adly, N., Alhashem, A., Ammari, A., Alkuraya, F. S.Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX. Hum. Mutat. 35: 36-40, 2014. [PubMed: 24285566] [Full Text: https://doi.org/10.1002/humu.22477\]
Gurrieri, F., Franco, B., Toriello, H., Neri, G.Oral-facial-digital syndromes: review and diagnostic guidelines. Am. J. Med. Genet. 143A: 3314-3323, 2007. [PubMed: 17963220] [Full Text: https://doi.org/10.1002/ajmg.a.32032\]
Liu, C., Cummins, T. R., Tyrrell, L., Black, J. A., Waxman, S. G., Dib-Hajj, S. D.CAP-1A is a novel linker that binds clathrin and the voltage-gated sodium channel Nav1.8. Molec. Cell. Neurosci. 28: 636-649, 2005. [PubMed: 15797711] [Full Text: https://doi.org/10.1016/j.mcn.2004.11.007\]

Contributors:

Ada Hamosh - updated : 07/09/2014

Creation Date:

Dorothy S. Reilly : 8/30/2007

Edit History:

alopez : 07/09/2014
carol : 8/31/2007